Tammy, portrayed by Melissa McCarthy, is a down-on-her-luck, foul-mouthed woman struggling with life's challenges. Initially, her day goes from bad to worse when, while searching for Chapstick in her backseat, she accidentally hits a deer. Arriving late at her job at Topper Jacks, her boss, Keith (Ben Falcone), promptly fires her due to her disheveled appearance, which includes a bloody nose from the accident.
After her car breaks down, she returns home only to find her husband, Greg (Nat Faxon), enjoying a romantic dinner with their neighbor, Missi (Toni Collette). Heartbroken, Tammy decides to leave town, taking her grandmother Pearl (Susan Sarandon)'s car. Pearl, with her considerable stash of cash, insists on joining her. Despite her mother's concerns about Pearl's medication and plans for the Brookview Retirement Home, Pearl convinces Tammy to hit the road and indulge in some fun.
Their journey takes a wild turn as they bond over drinks and reckless behavior, even finding themselves in a park the next morning. Pearl's wish to visit Niagara Falls fuels their adventure, but things get complicated when they run into trouble, including a jet ski accident that they can't afford to fix. In Louisville, a romantic escapade between Pearl and a man named Earl (Gary Cole) leads to more chaos and reveals the complicated entanglements of their lives.
As Tammy tries to deal with the feelings of abandonment and her tumultuous family dynamics, they face legal troubles that stem from their reckless decisions. During a frantic moment fueled by desperation, Tammy resorts to robbing Topper Jacks to fund her escape, forging unexpected friendships with the employees, Becky ([Sarah Baker]) and Larry ([Rich Williams]).
After a series of wild events—including a dramatic Fourth of July party with an explosive send-off for the jet ski—Tammy finds herself in a spiral of confrontations with Pearl. The necessary grace of their relationship feels strained as Tammy grapples with painful truths from her childhood.
Just when it seems everything is unraveling, there comes the comic twist of miscommunication, and Pearl is discovered passed out rather than being dead. However, law enforcement doesn't take kindly to their misadventures, leading to Tammy's brief stint in prison.
Upon her release 38 days later, her father (Dan Aykroyd) offers a darkly humorous support, suggesting extreme measures against Greg, while further revelations about family secrets surface.
Tammy eventually returns home to confront her tumultuous past, only to discover her grandmother is adapting well to life in the retirement home—and even has a new love interest! The closure comes when she decides to move closer to Bobby (Mark Duplass), the young man who shares a special connection with her.
As the credits roll, glimpses of new paths for all characters provide a comedic closure, illustrating the changing dynamics of love, family, and friendship in the most unconventional ways.
